Super-rapid disintegrating tablet, and method for producing same

ABSTRACT

An object of the present invention is to provide an orally disintegrating tablet (super-rapid disintegrating tablet) that is heavy and relatively thin, and has an extremely high disintegrability (short disintegration time), and a high tablet hardness, and to provide a simple method for the production of said super-rapid disintegrating tablet without such a complicated process as freeze-drying. 
     This invention relates to an orally disintegrating tablet having a specific surface area of from 1.50 to 4.00 mm 2 /mg and a weight of from 100 to 300 mg, particularly having a disintegration time in water of 7 seconds or less and an oral disintegration time of 6 seconds or less, a method for the production of said orally disintegrating tablet, and to a disintegrative particulate composition for use in said method.

TECHNICAL FIELD

The present invention relates to an orally disintegrating tablet havingan extremely short disintegration time in an oral cavity and/or inwater, which is heavy and relatively thin, and to a method for producingthe tablet.

BACKGROUND ART

In the past, orally disintegrating tablets have been developed as highlyconvenient forms which can safely be taken by patients who havedifficulty in swallowing drugs, elderly people, children, etc., andwhich can easily be taken without water. It is important that the orallydisintegrating tablets have sufficient breaking strength (tablethardness) such that any cracks, powdering, etc. are not caused in thetablets during production or transportation of the tablets or duringbreaking their seals in the same manner as general tablets, and also, itis important that the orally disintegrating tablets have excellentdisintegrability (disintegration time) such that the tablets immediatelydisintegrate in the oral cavity.

The tablet hardness and disintegrability are mutually opposingproperties. In general, when a molding pressure is increased to increasethe hardness, the disintegration time will tend to be prolonged, and,when the molding pressure is reduced to shorten the disintegration time,the hardness will tend to be smaller. Therefore, various technologieshave been developed in order to cope with both the two properties or toachieve an optimal balance between the two properties.

Furthermore, the components of particles, granulation methods, etc. havebeen studied in order to impart superior moldability to the particles orparticulate compositions constituting tablets.

It is well known that although the orally disintegrating tablets haveimproved medicine-taking compliance by patients, some patients havingtendency to strongly reject the taking of medicine would vomit thetablets having the oral disintegration time in a range of bout 20-30seconds. Accordingly, if a tablet has an extremely high disintegrabilitywith the disintegration time of a few seconds, it can be easilyadministered to said patients since it will be disintegrated before theymay feel uncomfortable when they take it.

Zydis (Registered Trademark) is known as a technique for the productionof such tablet having an extremely high oral disintegrability, that is,an “super-rapid disintegrating tablet.” This technique has beendeveloped by Cardinal Health Co. (Catalent Pharma Solutions, LLC) forthe production of an oral solid formulation. As shown in PTL 1, itcomprises preparing suspension of bulk (medicinal ingredient) andmannitol using gelatin as a supporting material and filling thesuspension into a blister, followed by freeze-drying to give a rapidlydispersing solid formulation for an oral administration.

Furthermore, PTL 2 discloses an invention relating to a method for theproduction of a multi-phasic, lyophilized, fast-dissolving dosage form.It is prepared by sequential dosing of a formulation containing aforming agent of non-gelling matrix and a formulation containing aforming agent of gelling gelatin, followed by freeze-drying to give amulti-phasic, lyophilized, fast-dissolving dosage form (FDDF) for thedelivery of a pharmaceutically active ingredient. For example,non-gelling gelatin and gelling gelatin are used for the forming agentsof non-gelling matrix and gelling matrix, respectively.

PTL 3 discloses an orally disintegrating tablet having a tablet hardnessof 10 N or more and a disintegration time in water of less than 15seconds, wherein its specific surface is of from 0.75 to 1.50 mm²/mg.

Although PTL 4-7 disclose various kinds of orally disintegrating tabletsas well, their specific surface is substantially in a range of from 0.75to 1.50 mm²/mg.

RELATED ARTS Patent Literature

PTL 1: Specification of Japanese Patent No. 4943581

PTL 2: JP-A-2013-522308

PTL 3 WO2015/005241 A1

PTL 4: JP-A-2002-179558

PTL 5 WO2007/018192 A1

PTL 6: JP-A-2008-285434

PTL 7: JP-A-2012-188364

SUMMARY OF INVENTION Problems to be Solved by the Invention

However, the above-mentioned conventional techniques would require aspecialized device for freeze-drying, and could not use a tablet machinefor the production of an usual tablet with a high production efficiency.And, the above ultrafast-disintegrating tablet produced by theconventional techniques has an extremely low tablet hardness. It hasbeen therefore desired an ultra-fast disintegrating tablet showing sucha level of tablet hardness as allowing for a usual PTP package.

Accordingly, an object of the present invention is to solve suchtechnical problems as found in the conventional ultrafast-disintegratingtablet, and thus, is to provide an orally disintegrating tablet(ultrafast (super rapid)-disintegrating tablet) having such an extremelyhigh disintegrability (short disintegration time) that a patient'staking of medicine can be certainly confirmed, and such a high tablethardness that cracking and lacking of the tablet is expected to bereduced to a practical level. A further object of the present inventionis to provide a simple method for the production of saidultrafast-disintegrating tablet without a complicated process such asfreeze-drying.

Means to Solve the Problem

The present inventors found that an ultrafast-disintegrating tablet thatis heavy and relatively thin has an extremely high disintegrability canbe obtained in the conventional granulation step, by using a particularrange of properties such as weight and specific surface area of theultrafast-disintegrating tablet, leading to completion of thisinvention.

More specifically, the present invention is to provide the followingaspects.

[Aspect 1]

An orally disintegrating tablet having a specific surface area of from1.50 to 4.00 mm²/mg and a weight of from 100 to 300 mg.

[Aspect 2]

The orally disintegrating tablet according to Aspect 1, which has adiameter of 12 mm or more.

[Aspect 3]

The orally disintegrating tablet according to Aspect 1 or 2, having atablet hardness of from 5 N to 30 N.

[Aspect 4]

The orally disintegrating tablet according to any one of Aspects 1 to 3,having a disintegration time in water of 7 seconds or less and an oraldisintegration time of 6 seconds or less.

[Aspect 5]

The orally disintegrating tablet according to any one of Aspects 1 to 4,which comprises a first disintegrator component of an acid-typecarboxymethylcellulose.

[Aspect 6]

The orally disintegrating tablet according to Aspect 5, which furthercomprises crystalline cellulose.

[Aspect 7]

A method for the production of the orally disintegrating tabletaccording to any one of Aspects 1 to 6, comprising mixing adisintegrative particulate composition with a medicinal ingredient, andsubjecting the resulting mixture to tableting.

[Aspect 8]

The method for the production of the orally disintegrating tabletaccording to Aspect 7, comprising a wet granulation step in theproduction of the disintegrative particulate composition.

[Aspect 9]

The method for the production of the orally disintegrating' tabletaccording to Aspect 7 or 8, comprising a two-stage granulation step inthe production of the disintegrative particulate composition.

[Aspect 10]

The method for the production of the orally disintegrating tabletaccording to any one of Aspects 7 to 9, wherein the tableting is carriedout at a tablet compression force of from 2 to 20 kN.

[Aspect 11]

A disintegrative particulate composition comprising a firstdisintegrator component of an acid-type carboxymethylcellulose, for usein the method for the production of the orally disintegrating tabletaccording to any one of Aspects 7 to 10.

[Aspect 12]

The disintegrative particulate composition according to Aspect 11,further comprising crystalline cellulose.

Advantageous Effects of Invention

According to the present invention, the ultrafast-disintegrating tabletthat is heavy and relatively thin and has an extremely shortdisintegration time in an oral cavity and/or in water can be easilyproduced by means of such a device as used for the conventional tablets.

BRIEF EXPLANATION OF DRAWINGS

FIG. 1 shows a method for the calculation of the surface area of theorally disintegrating tablet (a tablet having R surface) according tothe present invention.

DESCRIPTION OF EMBODIMENTS

The orally disintegrating tablet according to the present invention ischaracterized by having the specific surface area of from about 1.50 to4.00 mm²/mg, preferably of from about 1.50 to 3.50 mm²/mg, and theweight of from about 100 to 300 mg, preferably of from about 100 to 200mg.

The specific surface area means “surface area/the weight of a tablet.”The surface area can be obtained by a conventional method usually done.In the case of a flat tablet, for example, it is obtained by calculatinga sum of surface areas of the upper and lower circle parts and sidesurface (as a surface area of a round column). The specific surface areaof the tablet having R surface can be obtained by the calculation shownin FIG. 1.

There is no limitation in a tablet shape in the present invention, andany shape known in the art may be adopted, such as truly flat tablet,standard R surface, sugar-coating R surface, round-corner (edge) flattablet, angled-corner flat tablet (flat with bevel edge) and two-stage Rsurface. The diameter of the tablet may be optionally determined,usually being about 12 mm or more, for example, from about 12 to 18 mm.The thickness of the tablet is usually from about 0.50 mm to 1.80 mm,which is relatively thin.

From a view point of a production and use of the tablet, it is necessaryfor the tablet to have a relatively high hardness, being usually about 5N or more, preferably from about 5 N to 30 N, more preferably from about5 N to 21 N.

It is desired to make the time for the progress of disintegration tosuch an extent that patients could not vomit the tablet administered anymore, so that the patients won't feel uncomfortable and their vomit ofthe tablet will be inhibited. It is also desired to complete thedisintegration and administration of the tablet as soon as possible sothat the following administrations won't be rejected by the patient. Dueto the above features, the tablet according to the present inventionshows an extremely high disintegrability, such as the disintegrationtime in water of about 7 seconds or less, preferably 5 seconds or less,and the oral disintegration time (the disintegration time in an oralcavity) of 6 seconds or less, preferably 5 seconds or less, and willmeet the above requirements.

Values of these physical properties were measured based on the followingconditions/methods.

The medicinal ingredient comprised in the orally disintegrating tabletaccording to the present invention includes a pharmaceutical ingredient,and nutrient ingredient comprised in foods and health food products. Themedicinal ingredient may be added as such or in a coated or granulatedform for the purpose of sustained release or masking of bitterness ofthe medicinal ingredient.

There is no limitation on the application or kind of the medicinalingredients comprised in the orally disintegrating tablet according tothe present invention, which may include, for example, agents affectingeach organ such as the central nervous system, peripheral nervoussystem, a sensory organ, a circulatory organ, a respiratory organ and adigestive organ and an urogenital organ; hormone drug; agents affectingmetabolism such as a vitamin drug, an analeptic, an agent affectingblood and body fluid; agents affecting the function of tissue and cellsuch as an agent activating cellular function, an agent affectingtumors, an radioactive medicine, an anti-allergic agent; medicines basedon a medical prescription relating to herbal medicines and Chinesemedicines; antibiotics; agents for chemotherapy, biological drug; agentsfor pathogenic organisms such as parasites; agents for dispersing use,diagnosis, public health and external diagnosis.

In addition to the above medicinal ingredients, the orallydisintegrating tablet according to the present invention may optionallyinclude other pharmaceutically-acceptable components such as excipients,surfactants, lubricants, acidulants, sweeteners, corrigents, flavoringagents, colorants, and stabilizing agents, when needed. For example, asdescribed in the examples of the present specification, light silicicacid anhydride and/or β-cyclodextrin may be added in order to improveflowability, to add sweetness, etc. As these optional components, forexample, appropriate ingredients described in “Japanese PharmaceuticalExcipients Directory” (YAKUJI NIPPO LIMITED) or the JapanesePharmacopoeia can be used. Also, the blending ratios of each ingredient(component) are not particularly limited as long as the expected effectsof the present invention are brought about, and the blending ratios canproperly be determined by those skilled in the art. Furthermore, thetablet can comprise various disintegrators comprised in the followingdisintegrative particulate composition. The orally disintegrating tabletcan be formulated by any methods known to those skilled in the art, forexample, by tableting.

One of the preferable methods for the production of the orallydisintegrating tablet comprises mixing the disintegrative particulatecomposition with the medicinal ingredient (or a pharmaceuticalcomposition containing the medicinal ingredient) and other optionalcomponents, and subjecting the resulting mixture to tableting by meansof any suitable tableting machine known in the art at a tabletcompression force of from about 2 to 20 kN, preferably of from about 5to 20 kN. Alternatively, an “externally lubricating tableting method”may be adopted, wherein a lubricant such as magnesium stearate issprayed or applied in advance on a mortar and pestle of the tabletingmachine. The present invention therefore concerns the disintegrativeparticulate composition for use in the above method as well.

There is no limitation on the conditions (states) of the medicinalingredients and the like, being, for example, a powdered form. Mixing(solid trituration) of the disintegrative particulate composition withthe medicinal ingredient and tableting may be carried out by any methodor means known to those skilled in the art. An amount of the activeingredients in the orally disintegrating tablet may be controlled to asuitable administration dose during the above steps depending on asubject, purpose and the like for the administration.

Four mechanisms of “wicking”, “swelling”, “deformation” and “repulsion”have been proposed as mechanisms of disintegration of tablets or thelike. Among them, “wicking” is a disintegration mechanism which proceedsupon weakened binding force between particles included in the tablet asa result of water permeation through components such as disintegratorsincluded in the tablet. As atypical example of a disintegrator having ahigher effect to promote such “wicking”, an acid-typecarboxymethylcellulose has been known. Also, “swelling” is adisintegration mechanism which proceeds upon swelling of disintegratorsthemselves as a result of water permeation through the disintegrators.

The disintegrative particulate composition of the present inventionpreferably comprises the acid-type carboxymethylcellulose as the firstdisintegrator component, which is a substance called carmellose, and hasbeen used as a pharmaceutical additive. In the same manner as theacid-type carboxymethylcellulose, for example, both a calcium salt ofcarboxymethylcellulose and a cross-linked product of sodiumcarboxymethylcellulose are water-insoluble, and have been used asdisintegrator for tablets, etc. On the other hand, a sodium salt ofcarboxymethylcellulose is water-soluble, and has been used for purposesof a binder, etc. In addition, in some cases, a salt ofcarboxymethylcellulose may be referred to as carmellose.

For the second disintegrator component of the disintegrative particulatecomposition of the present invention, any disintegrators other than theacid-type carboxymethylcellulose which have been known to those skilledin the art can be used. However, in order to obtain combined effects ofthe different disintegration mechanisms as shown above, it is preferablethat a disintegrator having a superior effect to promote a mechanismother than “wicking” (e.g. “swelling”) be used as the seconddisintegrator component. Suitable examples of such a disintegratorinclude crospovidone, sodium croscarmellose, sodium carboxymethylstarch, low substituted hydroxypropylcellulose, calciumcarboxymethylcellulose, hydroxypropyl starch, and starch. Additionally,“crospovidone” is a common name fora cross-linked polymer of1-vinyl-2-pyrrolidone, and “sodium croscarmellose” is a common name fora cross-linked product of sodium carboxymethylcellulose.

Among them, one, or any combination of two or more components selectedfrom crospovidone, sodium croscarmellose, sodium carboxymethyl starch,low substituted hydroxypropylcellulose and calciumcarboxymethylcellulose is preferable.

The disintegrative particulate composition further comprises anexcipient. Typical examples of the excipient are sugars or sugaralcohols such as mannitol, erythritol, sorbitol, D-glucitol (maltitol),xylitol, trehalose, lactose, maltose, and. Moreover, as preferableexamples thereof, mannitol erythritol, trehalose, sorbitol andD-glucitol (maltitol) can be mentioned. As the excipient, two or moretypes of compounds properly selected from these compounds may also beused.

The disintegrative particulate composition further comprises crystallinecellulose known to those skilled in the art in order to further improvethe properties of the present disintegrating tablet. As typical examplesof such crystalline cellulose, commercially-available products such as“Avicel” (FMC Corporation), “CEOLUS” (Asahi Kasei Chemicals Corp.), and“VIVAPUR” (RETTENMAIER) can be mentioned.

Furthermore, various types of optional components known to those skilledin the art may properly be added and mixed into the disintegrativeparticulate composition of the present invention, for the purpose ofadjusting various characteristics such as the disintegrating force,binding force and ease in taking the tablet. As examples of suchcomponents, fluidizing agents, sweetening agents, flavoring agents andcoloring agents can be mentioned.

The amount of each component blended in the disintegrative particulatecomposition of the present invention can properly be determined by thoseskilled in the art, depending on, for example, a type of the component,a type and purpose of the medicinal ingredient for which thedisintegrative particulate composition is to be used, or a purpose ofthe final product, i.e. the orally disintegrating tablet. In general,relative to a total weight of the disintegrative particulatecomposition, the amount of the first disintegrator component is within arange of 10% to 50% by weight, the amount of the second disintegratorcomponent is within a range of 1% to 20% by weight, the amount of theexcipient is within a range of 30 to 88% by weight, and the amount ofthe crystalline cellulose is within a range of 1% to 40% by weight.

The disintegrative particulate composition according to the presentinvention may be produced by any method known to those skilled in theart. For example, it may be produced by a two-stage granulation stepcomprising a first wet granulation step using any one or two of thethree components and a second wet granulation step using at least thegranules obtained in the first wet granulation step and the remainingcomponent(s) not used in the first wet granulation step, or athree-stage granulation step further comprising a third step of mixingother components with the granules obtained in the second wetgranulation step.

Furthermore, the disintegrative particulate composition according to thepresent invention may be produced by one granulation step using all ofthe components together.

In each method of the above production method, each granulation step iscarried out by a method in which each component is dispersed in thepresence of water, and the dispersion is dried to form complexes, i.e.by a wet granulation process. As specific examples of a wet granulationprocess, spray methods such as spray drying, tumbling granulation,agitation granulation and fluidized-bed granulation; the freeze-dryingmethod; kneading granulation, and the like can be mentioned. Thecomposition can be produced by any of these methods known to thoseskilled in the art.

Since disintegrators such as an acid-type carboxymethylcellulose arehydrophilic, by carrying out a manipulation of applying a physical forcesuch as by agitation or the like in the presence of water according tothe wet granulation, the aggregated state in the dry powder will convertinto a state in which particles are more dispersed. Dispersion can mosteasily be carried out by the fluidized-bed granulation process in whichdispersion by water spraying and drying are carried out, spray drying,tumbling granulation, agitation granulation, etc., and also, dryingspeeds in these methods are high. Therefore, these methods arepreferable.

Among them, the fluidized-bed granulation process is a granulationmethod in which water, an aqueous solution including a binder, or thelike is sprayed onto powder, while blowing the powder up by hot air, andadjustment of spraying conditions, etc. is easy in this method.Therefore, the fluidized-bed granulation process is the most preferablemethod.

Furthermore, those skilled in the art can properly determine variousconditions in each granulation step, such as the spraying speed, thesupply air temperature, the exhaust temperature, and the air supplyrate, depending on types or amounts of the components, etc.

In each granulation step, as a medium for the spray liquid, a solventacceptable in pharmaceuticals or foods, such as water, ethanol, methanolor acetone, can be mentioned. Alternatively, as the spray liquid, forexample, an aqueous solution in which less than 10% of the component(s)for the disintegrative particulate composition is dissolved can bementioned, and, in particular, water or such an aqueous solution ispreferable.

It is preferable that the disintegrative particulate composition of thepresent invention have the following physical properties:

-   (1) an average particle size of 50 to 200 microns; and-   (2) a water content of 0.5% to 6% by weight.

In addition, these physical properties are measured by using thefollowing methods and conditions.

The average particle size: 2 g of the disintegrative particulatecomposition is subjected to a measurement with a ϕ75 mm automaticshaking sieve device (Type “M-2”, Tsutsui Scientific Instruments Co.,Ltd.).

The water content: 5 g of the disintegrative particulate composition issubjected to a measurement using a halogen water content measuringdevice (Type “HB43”, METTLER TOLEDO K.K.).

In addition, contents of all related art documents cited in the presentspecification are incorporated herein by reference.

Hereinafter, the present invention will more specifically be describedwith reference to Examples. However, the present invention is notconsidered to be limited to the Examples.

EXAMPLES Example 1 (Production of the Disintegrative ParticulateComposition)

In the first wet granulation step, 280 g of mannitol (D-mannitol, MerckLtd.), 75 g of carmellose (NS-300, GOTOKU CHEMICAL CO., LTD.) and 100 gof a crystalline cellulose (CEOLUS PH-101, Asahi Kasei Chemicals Corp.)were charged to a fluidized-bed granulator (LAB-1, Powrex Corporation),and 240 g of purified water was sprayed onto the resulting mixture at arate of 24 g/minute to thereby obtain granules. In the second wetgranulation step, 40 g of crospovidone (Polyplasdone INF-10, ISP Japan)was added to the granules and 300 g of purified water was sprayed ontothe resulting mixture at a rate of 10 g/minute to thereby obtaingranules (a disintegrative particulate composition of the presentinvention). The resulting granules had the following values for physicalproperties: (1) an average particle size of 93 microns and (2) a watercontent of 2.3% by weight.

Example 2 (Production of the Orally Disintegrating Tablet 1)

0.5 parts by weight of magnesium stearate (Taihei Chemical IndustrialCo. Ltd.) was mixed with 99.5 parts by weight of the disintegrativeparticulate composition obtained in Example 1 (Production of thedisintegrative particulate composition). The mixture was then subjectedto tableting at tablet compression force of 18 kN with a hand-presstableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to therebyobtain a truly flat tablet having a diameter of 14.0 mm, thickness of0.80 mm and a weight of from 150 mg.

Example 3 (Production of the Orally Disintegrating Tablet 2)

0.5 parts by weight of magnesium stearate was mixed with 99.5 parts byweight of the disintegrative particulate composition obtained in Example1 (Production of the disintegrative particulate composition). Themixture was then subjected to tableting at tablet compression force of18kN with the hand-press tableting machine to thereby obtain a trulyflat tablet having a diameter of 14.0 mm, thickness of 1.07 mm and aweight of from 200 mg.

Example 4 (Production of the Orally Disintegrating Tablet 3)

0.2 parts by weight of magnesium stearate was mixed with 99.8 parts byweight of the disintegrative particulate composition obtained in Example1 (Production of the disintegrative particulate composition). Themixture was then subjected to tableting at tablet compression force of 8kN with the hand-press tableting machine to thereby obtain a truly flattablet having a diameter of 14.0 mm, thickness of 1.51 mm and a weightof from 250 mg.

Example 5 (Production of the Orally Disintegrating Tablet 4)

0.2 parts by weight of magnesium stearate was mixed with 99.8 parts byweight of the disintegrative particulate composition obtained in Example1 (Production of the disintegrative particulate composition). Themixture was then subjected to tableting at tablet compression force of18 kN with the hand-press tableting machine to thereby obtain a trulyflat tablet having a diameter of 14.0 mm, thickness of 0.55 mm and aweight of from 100 mg.

Example 6 (Production of the Orally Disintegrating Tablet 5)

10.0 parts by weight of ascorbic acid, 1.0 parts by weights of lightsilicic acid anhydride and 0.5 parts by weight of magnesium stearatewere mixed with 88.5 parts by weight of the disintegrative particulatecomposition obtained in Example 1 (Production of the disintegrativeparticulate composition). The mixture was then subjected to tableting attablet compression force of 18 kN with a rotating tableting machine(HT-EX12SS-U, HATA TEKKOSHO CO., LTD.) to thereby obtain a truly flattablet having a diameter of 14.0 mm, thickness of 0.78 mm and a weightof from 150 mg.

Example 7 (Production of the Orally Disintegrating Tablet 6)

40.0 parts by weight of β-cyclodextrin and 0.5 parts by weight ofmagnesium stearate were mixed with 59.5 parts by weight of thedisintegrative particulate composition obtained in Example 1 (Productionof the disintegrative particulate composition). The mixture was thensubjected to tableting at tablet compression force of 8 kN with therotating tableting machine (HT-EX12SS-U, HATA TEKKOSHO CO., LTD.) tothereby obtain a truly flat tablet having a diameter of 14.0 mm,thickness of 0.87 mm and a weight of from 150 mg.

Example 8 (Production of the Orally Disintegrating Tablet 7)

4.2 parts by weight of crospovidone XL and 0.5 parts by weight ofmagnesium stearate were mixed with 95.3 parts by weight of thedisintegrative particulate composition obtained in Example 1 (Productionof the disintegrative particulate composition). The mixture was thensubjected to tableting at tablet compression force of 18 kN with thehand-press tableting machine to thereby obtain a truly flat tablethaving a diameter of 14.0 mm, thickness of 0.81 mm and a weight of from150 mg.

Example 9 (Production of the Orally Disintegrating Tablet 8)

12.4 parts by weight of carmellose and 0.5 parts by weight of magnesiumstearate were mixed with 89.5 parts by weight of the disintegrativeparticulate composition obtained in Example 1 (Production of thedisintegrative particulate composition). The mixture was then subjectedto tableting at tablet compression force of 18 kN with the hand-presstableting machine to thereby obtain a truly flat tablet having adiameter of 14.0 mm, thickness of 0.80 mm and a weight of from 150 mg.

Example 10 (Production of the Orally Disintegrating Tablet 9)

2.0 parts by weight of sodium croscarmellose and 0.5 parts by weight ofmagnesium stearate were mixed with 97.5 parts by weight of thedisintegrative particulate composition obtained in Example 1 (Productionof the disintegrative particulate composition). The mixture was thensubjected to tableting at tablet compression force of 18 kN with thehand-press tableting machine to thereby obtain a truly flat tablethaving a diameter of 14.0 mm, thickness of 0.81 mm and a weight of from150 mg.

Example 11 (Production of the Orally Disintegrating Tablet 10)

10.0 parts by weight of L-HPC and 0.5 parts by weight of magnesiumstearate were mixed with 89.5 parts by weight of the disintegrativeparticulate composition obtained in Example 1 (Production of thedisintegrative particulate composition). The mixture was then subjectedto tableting at tablet compression force of 18 kN with the hand-presstableting machine to thereby obtain a truly flat tablet having adiameter of 14.0 mm, thickness of 0.81 mm and a weight of from 150 mg.

Example 12 (Production of the Orally Disintegrating Tablet 11)

30.0 parts by weight of Ethenzamide, 1.0 parts by weight of lightsilicic acid anhydride and 0.3 parts by weight of magnesium stearatewere mixed with 69.7 parts by weight of the disintegrative particulatecomposition obtained in Example 1 (Production of the disintegrativeparticulate composition). The mixture was then subjected to tableting attablet compression force of 18 kN with the rotating tableting machine(HT-EX12SS-U, HATA TEKKOSHO CO., LTD.) to thereby obtain a truly flattablet having a diameter of 14.0 mm, thickness of 0.80 mm and a weightof from 150 mg.

Example 13 (Production of the Orally Disintegrating Tablet 12)

10.0 parts by weight of acetaminophen, 1.0 parts by weight of lightsilicic acid anhydride and 0.7 parts by weight of magnesium stearatewere mixed with 88.3 parts by weight of the disintegrative particulatecomposition obtained in Example 1 (Production of the disintegrativeparticulate composition). The mixture was then subjected to tableting attablet compression force of 18 kN with the rotating tableting machine(HT-EX12SS-U, HATA TEKKOSHO CO., LTD.) to thereby obtain a truly flattablet having a diameter of 14.0 mm, thickness of 0.82 mm and a weightof from 150 mg.

Hardness and Disintegration time in water of each tablet obtained inExamples and Comparative Examples were measured based on the followingconditions/methods. The values measured are shown in Table 1 below.

Values of these physical properties were measured based on the followingconditions/methods.

Hardness: a hardness (N) was measured with a Kiya hardness tester(Fujiwara Scientific Company Co., Ltd.).

Disintegration time in water: a disintegration time in water wasmeasured with a disintegration tester (NT-400, TOYAMA SANGYO CO., LTD.)in accordance with the method described in the Japanese Pharmacopoeiaprovided that an auxiliary disk was not used.

Disintegration time in an oral cavity: an oral disintegration time(disintegration time in an oral cavity) in water was measured with adisintegration tester (Tricorptester, OKADA SEIKO CO., LTD.)

When the measurement with Tricorptester was difficult, a tablet wastaken in the oral cavity, and, while keeping a state in which the tabletwas placed between the tongue and the upper jaw without applying anypressure thereto, the time required for the tablet to be completelydisintegrated was measured. The measurements were each repeated threetimes by a few adults of both sexes, and average values thereof wereregarded as measurement results.

The measurements for the hardness and disintegration time were eachrepeated six times, and average values thereof were regarded asmeasurement results.

[Measured Values of the Physical Properties]

The physical properties of the tablets in Examples 2-13 are shown inTable 1.

TABLE 1 Example 2 Example 3 Example 4 Example 5 Tablet Weight (mg) 150200 250 100 Tablet compression Force (kN) 18 18 8 18 Specific SurfaceArea (mm²/mg) 2.29 1.77 1.50 3.32 Tablet Hardness (N) 11.3 19.4 14.7 7.5Disintegration time in water (seconds) 3.4 5.5 5.0 2.9 OralDisintegration time (seconds) 4.4 4.7 5.9 2.7 Example 6 Example 7Example 8 Example 9 Tablet Weight (mg) 150 150 150 150 Tabletcompression Force (kN) 18 8 18 18 Specific Surface Area (mm²/mg) 2.282.31 2.29 2.29 Tablet Hardness (N) 12.5 20.1 12.4 10.9 Disintegrationtime in water (seconds) 6.2 2.7 3.5 3.6 Oral Disintegration time(seconds) 3.6 3.2 4.5 4.9 Example 10 Example 11 Example 12 Example 13Tablet Weight (mg) 150 150 150 150 Tablet compression Force (kN) 18 1818 18 Specific Surface Area (mm²/mg) 2.29 2.29 2.29 2.29 Tablet Hardness(N) 13.6 15.5 18.0 13.7 Disintegration time in water (seconds) 2.8 3.15.8 5.5 Oral Disintegration time (seconds) 4.3 4.6 5.7 6.1

The data in Table 1 show that the orally disintegrating tablet accordingto the present invention has such an excellent disintegrability such asthe extremely short disintegration time in water and in the oral cavity.

INDUSTRIAL APPLICABILITY

The present invention has enabled to provide an orally disintegratingtablet (the ultrafast-disintegrating tablet) that is heavy andrelatively thin, and has not only advantages that it can safely be takenby patients who have difficulty in swallowing drugs, elderly people,children, etc. and can easily be taken without water, but also furtheradvantages that it has such an extremely high disintegrability (shortdisintegration time) that the taking of medicine by patients havingtendency to strongly reject it can be certainly confirmed, and such ahigh tablet hardness that cracking and lacking of the tablet is expectedto be reduced to a practical level.

1. An orally disintegrating tablet having a specific surface area offrom 1.50 to 4.00 mm²/mg and a weight of from 100 to 300 mg.
 2. Theorally disintegrating tablet according to claim 1, which has a diam etcof 12 mm or more.
 3. The orally disintegrating tablet according to claim1, having a tablet hardness of from 5 N to 30 N.
 4. The orallydisintegrating tablet according to claim 1, having a disintegration timein water of 7 seconds or less and an oral disintegration time of 6seconds or less.
 5. The orally disintegrating tablet according to claim1, which comprises a first disintegrator component of an acid-typecarboxymethylcellulose.
 6. The orally disintegrating tablet according toclaim 5, which further comprises crystalline cellulose.
 7. A method forthe production of the orally disintegrating tablet according to claim 1,comprising mixing a disintegrative particulate composition with amedicinal ingredient, and subjecting the resulting mixture to tableting.8. The method for the production of the orally disintegrating tabletaccording to claim 7, comprising a wet granulation step in theproduction of the disintegrative particulate composition.
 9. The methodfor the production of the orally disintegrating tablet according toclaim 7, comprising a two-stage granulation step in the production ofthe disintegrative particulate composition.
 10. The method for theproduction of the orally disintegrating tablet according to claim 7,wherein the tableting is carried out at a tablet compression force offrom 2 to 20 kN. 11-12. (canceled)
 13. The orally disintegrating tabletaccording to claim 2, having a tablet hardness of from 5 N to 30 N. 14.The orally disintegrating tablet according to claim 2, having adisintegration time in water of 7 seconds or less and an oraldisintegration time of 6 seconds or less.
 15. The orally disintegratingtablet according to claim 3, having a disintegration time in water of 7seconds or less and an oral disintegration time of 6 seconds or less.16. The orally disintegrating tablet according to claim 2, whichcomprises a first disintegrator component of an acid-typecarboxymethylcellulose.
 17. The orally disintegrating tablet accordingto claim 3, which comprises a first disintegrator component of anacid-type carboxymethylcellulose.
 18. The orally disintegrating tabletaccording to claim 4, which comprises a first disintegrator component ofan acid-type carboxymethylcellulose.
 19. The method for the productionof the orally disintegrating tablet according to claim 8, comprising atwo-stage granulation step in the production of the disintegrativeparticulate composition.
 20. The method for the production of the orallydisintegrating tablet according to claim 8, wherein the tableting iscarried out at a tablet compression force of from 2 to 20 kN.
 21. Themethod tbr the production of the orally disintegrating tablet accordingto claim 9, wherein the tableting is carried out at a tablet compressionforce of from 2 to 20 kN.